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T cells can contribute to clearance of respiratory viruses that cause acute-resolving infections such as SARS-CoV-2, helping to provide long-lived protection against disease. Recent studies have suggested an additional role for T cells in resisting overt infection: pre-existing cross-reactive responses were preferentially enriched in healthcare workers who had abortive infections1, and in household contacts protected from infection2. We hypothesize that such early viral control would require pre-existing cross-reactive memory T cells already resident at the site of infection; such airway-resident responses have been shown to be critical for mediating protection after intranasal vaccination in a murine model of SARS-CoV3. Bronchoalveolar lavage samples from the lower respiratory tract of healthy donors obtained before the COVID-19 pandemic revealed airway-resident, SARS-CoV-2-cross-reactive T cells, which correlated with the strength of human seasonal coronavirus immunity. We therefore demonstrate the potential to harness functional airway-resident SARS-CoV-2-reactive T cells in next-generation mucosal vaccines.
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COVID-19 , SARS-CoV-2 , Animais , Anticorpos Antivirais , Reações Cruzadas , Humanos , Camundongos , Pandemias , Sistema RespiratórioRESUMO
The liver is bathed in bacterial products, including lipopolysaccharide transported from the intestinal portal vasculature, but maintains a state of tolerance that is exploited by persistent pathogens and tumours1-4. The cellular basis mediating this tolerance, yet allowing a switch to immunity or immunopathology, needs to be better understood for successful immunotherapy of liver diseases. Here we show that a variable proportion of CD8+ T cells compartmentalized in the human liver co-stain for CD14 and other prototypic myeloid membrane proteins and are enriched in close proximity to CD14high myeloid cells in hepatic zone 2. CD14+CD8+ T cells preferentially accumulate within the donor pool in liver allografts, among hepatic virus-specific and tumour-infiltrating responses, and in cirrhotic ascites. CD14+CD8+ T cells exhibit increased turnover, activation and constitutive immunomodulatory features with high homeostatic IL-10 and IL-2 production ex vivo, and enhanced antiviral/anti-tumour effector function after TCR engagement. This CD14+CD8+ T cell profile can be recapitulated by the acquisition of membrane proteins-including the lipopolysaccharide receptor complex-from mononuclear phagocytes, resulting in augmented tumour killing by TCR-redirected T cells in vitro. CD14+CD8+ T cells express integrins and chemokine receptors that favour interactions with the local stroma, which can promote their induction through CXCL12. Lipopolysaccharide can also increase the frequency of CD14+CD8+ T cells in vitro and in vivo, and skew their function towards the production of chemotactic and regenerative cytokines. Thus, bacterial products in the gut-liver axis and tissue stromal factors can tune liver immunity by driving myeloid instruction of CD8+ T cells with immunomodulatory ability.
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Linfócitos T CD8-Positivos , Tolerância Imunológica , Receptores de Lipopolissacarídeos , Lipopolissacarídeos , Fígado , Células Mieloides , Humanos , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/imunologia , Lipopolissacarídeos/farmacologia , Células Mieloides/imunologia , Células Mieloides/metabolismo , Neoplasias/imunologia , Neoplasias/patologia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Tolerância Imunológica/efeitos dos fármacos , Tolerância Imunológica/imunologia , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/patologia , Fígado/virologia , Interleucina-2/biossíntese , Interleucina-2/imunologia , Quimiotaxia de Leucócito , Bactérias/imunologia , Intestinos/imunologia , Intestinos/microbiologiaRESUMO
Individuals with potential exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) do not necessarily develop PCR or antibody positivity, suggesting that some individuals may clear subclinical infection before seroconversion. T cells can contribute to the rapid clearance of SARS-CoV-2 and other coronavirus infections1-3. Here we hypothesize that pre-existing memory T cell responses, with cross-protective potential against SARS-CoV-2 (refs. 4-11), would expand in vivo to support rapid viral control, aborting infection. We measured SARS-CoV-2-reactive T cells, including those against the early transcribed replication-transcription complex (RTC)12,13, in intensively monitored healthcare workers (HCWs) who tested repeatedly negative according to PCR, antibody binding and neutralization assays (seronegative HCWs (SN-HCWs)). SN-HCWs had stronger, more multispecific memory T cells compared with a cohort of unexposed individuals from before the pandemic (prepandemic cohort), and these cells were more frequently directed against the RTC than the structural-protein-dominated responses observed after detectable infection (matched concurrent cohort). SN-HCWs with the strongest RTC-specific T cells had an increase in IFI27, a robust early innate signature of SARS-CoV-2 (ref. 14), suggesting abortive infection. RNA polymerase within RTC was the largest region of high sequence conservation across human seasonal coronaviruses (HCoV) and SARS-CoV-2 clades. RNA polymerase was preferentially targeted (among the regions tested) by T cells from prepandemic cohorts and SN-HCWs. RTC-epitope-specific T cells that cross-recognized HCoV variants were identified in SN-HCWs. Enriched pre-existing RNA-polymerase-specific T cells expanded in vivo to preferentially accumulate in the memory response after putative abortive compared to overt SARS-CoV-2 infection. Our data highlight RTC-specific T cells as targets for vaccines against endemic and emerging Coronaviridae.
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Infecções Assintomáticas , COVID-19/imunologia , COVID-19/virologia , RNA Polimerases Dirigidas por DNA/imunologia , Células T de Memória/imunologia , SARS-CoV-2/imunologia , Soroconversão , Proliferação de Células , Estudos de Coortes , RNA Polimerases Dirigidas por DNA/metabolismo , Evolução Molecular , Feminino , Pessoal de Saúde , Humanos , Masculino , Proteínas de Membrana/imunologia , Células T de Memória/citologia , Complexos Multienzimáticos/imunologia , SARS-CoV-2/enzimologia , SARS-CoV-2/crescimento & desenvolvimento , Transcrição Gênica/imunologiaRESUMO
Efficient immune protection against viruses such as SARS-CoV-2 requires the coordinated activity of innate immunity, B and T cells. Accumulating data point to a critical role for T cells not only in the clearance of established infection, but also for aborting viral replication independently of humoral immunity. Here we review the evidence supporting the contribution of antiviral T cells and consider which of their qualitative features favour efficient control of infection. We highlight how studies of SARS-CoV-2 and other coronaviridae in animals and humans have provided important lessons on the optimal timing (When), functionality and specificity (Which), and location (Where) of antiviral T cells. We discuss the clinical implications, particularly for the development of next-generation vaccines, and emphasise areas requiring further study.
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COVID-19 , SARS-CoV-2 , Animais , Humanos , Linfócitos T , Imunidade Humoral , Antivirais , Vacinação , Anticorpos AntiviraisRESUMO
High gestational weight gain (GWG) is a cardiovascular risk factor and may disturb neonatal endothelial function. Long non-coding RNAs (lncRNAs) regulate gene expression epigenetically and can modulate endothelial function. Endothelial colony forming cells (ECFCs), circulating endothelial precursors, are a recruitable source of endothelial cells and sustain endothelial function, vascular growth and repair. We here investigated whether higher GWG affects neonatal ECFC function and elucidated the role of lncRNAs herein. Wound healing of umbilical cord blood-derived ECFCs after pregnancies with GWG <13 kg versus >13 kg was determined in a scratch assay and based on monolayer impedance after electric wounding (electric cell-substrate impedance sensing, ECIS). LncRNA expression was analysed by RNA sequencing. The function of killer cell lectin-like receptor K1 antisense RNA (KLRK1-AS1) was investigated after siRNA-based knockdown. Closure of the scratch was delayed by 25% (P = 0.041) in the higher GWG group and correlated inversely with GWG (R = -0.538, P = 0.012) in all subjects (n = 22). Similarly, recovery of the monolayer barrier after electric wounding was delayed (-11% after 20 h; P = 0.014; n = 15). Several lncRNAs correlated with maternal GWG, the most significant one being KLRK1-AS1 (log2 fold change = -0.135, P < 0.001, n = 35). KLRK1-AS1 knockdown (n = 4) reduced barrier recovery after electric wounding by 21% (P = 0.029) and KLRK1-AS1 expression correlated with the time required for wound healing for both scratch (R = 0.447, P = 0.033) and impedance-based assay (R = 0.629, P = 0.014). Higher GWG reduces wound healing of neonatal ECFCs, and lower levels of the lncRNA KLRK1-AS1 may underlie this. KEY POINTS: Maternal cardiovascular risk factors such as diabetes, obesity and smoking in pregnancy disturb fetal endothelial function, and we here investigated whether also high gestational weight gain (GWG) has an impact on fetal endothelial cells. Circulating endothelial progenitor cells (endothelial colony forming cells, ECFCs) are highly abundant in the neonatal blood stream and serve as a circulating pool for vascular growth and repair. We revealed that higher GWG delays wound healing capacity of ECFCs in vitro. We identified the regulatory RNA lncRNA KLRK1-AS1 as a link between GWG and delayed ECFC wound healing. Our data show that high GWG, independent of pre-pregnancy BMI, affects neonatal ECFC function.
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Células Progenitoras Endoteliais , Ganho de Peso na Gestação , RNA Longo não Codificante , Gravidez , Recém-Nascido , Feminino , Humanos , RNA Longo não Codificante/genética , Células Cultivadas , Cicatrização , Subfamília K de Receptores Semelhantes a Lectina de Células NKRESUMO
BACKGROUND: The consumption of high-caloric diets strongly contributes to the development of non-communicable diseases (NCDs), including cardiovascular disease, the leading cause of mortality worldwide. Exercise (along with diet intervention) is one of the primary non-pharmacological approaches to promote a healthier lifestyle and counteract the rampant prevalence of NCDs. The present study evaluated the effects of exercise cessation after a short period training on the cardiac metabolic and mitochondrial function of female rats. METHODS: Seven-week-old female Sprague-Dawley rats were fed a control or a high-fat, high-sugar (HFHS) diet and, after 7 weeks, the animals were kept on a sedentary lifestyle or submitted to endurance exercise for 3 weeks (6 days per week, 20-60 min/day). The cardiac samples were analysed 8 weeks after exercise cessation. RESULTS: The consumption of the HFHS diet triggered impaired glucose tolerance, whereas the HFHS diet and physical exercise resulted in different responses in plasma adiponectin and leptin levels. Cardiac mitochondrial respiration efficiency was decreased by the HFHS diet consumption, which led to reduced ATP and increased NAD(P)H mitochondrial levels, which remained prevented by exercise 8 weeks after cessation. Exercise training-induced cardiac adaptations in redox balance, namely increased relative expression of Nrf2 and downstream antioxidant enzymes persist after an eight-week exercise cessation period. CONCLUSIONS: Endurance exercise modulated cardiac redox balance and mitochondrial efficiency in female rats fed a HFHS diet. These findings suggest that exercise may elicit cardiac adaptations crucial for its role as a non-pharmacological intervention for individuals at risk of developing NCDs.
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Maternal obesity (MO) is rising worldwide, affecting half of all gestations, constituting a possible risk-factor for some pregnancy-associated liver diseases (PALD) and hepatic diseases. PALD occur in approximately 3% of pregnancies and are characterized by maternal hepatic oxidative stress (OS) and mitochondrial dysfunction. Maternal hepatic disease increases maternal and fetal morbidity and mortality. Understanding the role of MO on liver function and pathophysiology could be crucial for better understanding the altered pathways leading to PALD and liver disease, possibly paving the way to prevention and adequate management of disease. We investigated specific hepatic metabolic alterations in mitochondria and oxidative stress during MO at late-gestation. Maternal hepatic tissue was collected at 90% gestation in Control and MO ewes (fed 150% of recommended nutrition starting 60 days before conception). Maternal hepatic redox state, mitochondrial respiratory chain (MRC), and OS markers were investigated. MO decreased MRC complex-II activity and its subunits SDHA and SDHB protein expression, increased complex-I and complex-IV activities despite reduced complex-IV subunit mtCO1 protein expression, and increased ATP synthase ATP5A subunit. Hepatic MO-metabolic remodeling was characterized by decreased adenine nucleotide translocator 1 and 2 (ANT-1/2) and voltage-dependent anion channel (VDAC) protein expression and protein kinase A (PKA) activity (P<0.01), and augmented NAD+/NADH ratio due to reduced NADH levels (P<0.01). MO showed an altered redox state with increased OS, increased lipid peroxidation (P<0.01), decreased GSH/GSSG ratio (P=0.005), increased superoxide dismutase (P=0.03) and decreased catalase (P=0.03) antioxidant enzymatic activities, lower catalase, glutathione peroxidase (GPX)-4 and glutathione reductase protein expression (P<0.05), and increased GPX-1 abundance (P=0.03). MO-related hepatic changes were more evident in the right lobe, corroborated by the integrative data analysis. Hepatic tissue from obese pregnant ewes showed alterations in the redox state, consistent with OS and MRC and metabolism remodeling. These are hallmarks of PALD and hepatic disease, supporting MO as a risk-factor and highlighting OS and mitochondrial dysfunction as mechanisms responsible for liver disease predisposition.
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Hepatopatias , NAD , Humanos , Feminino , Gravidez , Animais , Ovinos , Catalase/metabolismo , NAD/metabolismo , Fígado/metabolismo , Estresse Oxidativo , Obesidade/metabolismo , Antioxidantes/metabolismo , Hepatopatias/metabolismo , Superóxido Dismutase/metabolismo , Glutationa/metabolismoRESUMO
Intra-uterine growth restriction (IUGR) is a common cause of fetal/neonatal morbidity and mortality and is associated with increased offspring predisposition for cardiovascular disease (CVD) development. Mitochondria are essential organelles in maintaining cardiac function, and thus, fetal cardiac mitochondria could be responsive to the IUGR environment. In this study, we investigated whether in utero fetal cardiac mitochondrial programming can be detectable in an early stage of IUGR pregnancy. Using a well-established nonhuman IUGR primate model, we induced IUGR by reducing by 30% the maternal diet (MNR), both in males (MNR-M) and in female (MNR-F) fetuses. Fetal cardiac left ventricle (LV) tissue and blood were collected at 90 days of gestation (0.5 gestation, 0.5 G). Blood biochemical parameters were determined and heart LV mitochondrial biology assessed. MNR fetus biochemical blood parameters confirm an early fetal response to MNR. In addition, we show that in utero cardiac mitochondrial MNR adaptations are already detectable at this early stage, in a sex-divergent way. MNR induced alterations in the cardiac gene expression of oxidative phosphorylation (OXPHOS) subunits (mostly for complex-I, III, and ATP synthase), along with increased protein content for complex-I, -III, and -IV subunits only for MNR-M in comparison with male controls, highlight the fetal cardiac sex-divergent response to MNR. At this fetal stage, no major alterations were detected in mitochondrial DNA copy number nor markers for oxidative stress. This study shows that in 90-day nonhuman primate fetuses, a 30% decrease in maternal nutrition generated early in utero adaptations in fetal blood biochemical parameters and sex-specific alterations in cardiac left ventricle gene and protein expression profiles, affecting predominantly OXPHOS subunits. Since the OXPHOS system is determinant for energy production in mitochondria, our findings suggest that these early IUGR-induced mitochondrial adaptations play a role in offspring's mitochondrial dysfunction and can increase predisposition to CVD in a sex-specific way.
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Doenças Cardiovasculares , Desenvolvimento Fetal , Gravidez , Humanos , Animais , Masculino , Feminino , Feto/metabolismo , Retardo do Crescimento Fetal/metabolismo , Primatas , Nutrientes , Doenças Cardiovasculares/metabolismoRESUMO
Internal erosion is the most important failure mechanism of earth and rockfill dams. Since this type of erosion develops internally and silently, methodologies of data acquisition and processing for dam monitoring are crucial to guarantee a safe operation during the lifespan of these structures. In this context, artificial intelligence techniques show up as tools that can simplify the analysis and verification process not of the internal erosion itself, but of the effects that this pathology causes in the response of the dam to external stimuli. Therefore, within the scope of this paper, a methodological framework for monitoring internal erosion in the body of earth and rockfill dams will be proposed. For that, artificial intelligence methods, especially deep neural autoencoders, will be used to treat the acoustic data collected by geophones installed on a dam. The sensor data is processed to identify patterns and anomalies as well as to classify the dam's structural health status. In short, the acoustic dataset is preprocessed to reduce its dimensionality. In this process, for each second of acquired data, three parameters are calculated (Hjorth parameters). For each parameter, the data from all the available sensors are used to calibrate an autoencoder. Then, the reconstruction error of each autoencoder is used to monitor how far from the original (normal) state the acoustic signature of the dam is. The time series of reconstruction errors are combined with a cumulative sum (CUSUM) algorithm, which indicates changes in the sequential data collected. Additionally, the outputs of the CUSUM algorithms are treated by a fuzzy logic framework to predict the status of the structure. A scale model is built and monitored to check the effectiveness of the methodology hereby developed, showing that the existence of anomalies is promptly detected by the algorithm. The framework introduced in the present paper aims to detect internal erosion inside dams by combining different techniques in a novel context and methodological workflow. Therefore, this paper seeks to close gaps in prior studies, which mostly treated just parts of the data acquisition-processing workflow.
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Inteligência Artificial , Lógica Fuzzy , Acústica , Algoritmos , Redes Neurais de ComputaçãoRESUMO
Embryonic and foetal development are critical periods of development in which several environmental cues determine health and disease in adulthood. Maternal conditions and an unfavourable intrauterine environment impact foetal development and may programme the offspring for increased predisposition to metabolic diseases and other chronic pathologic conditions throughout adult life. Previously, non-communicable chronic diseases were only associated with genetics and lifestyle. Now the origins of non-communicable chronic diseases are associated with early-life adaptations that produce long-term dysfunction. Early-life environment sets the long-term health and disease risk and can span through multiple generations. Recent research in developmental programming aims at identifying the molecular mechanisms responsible for developmental programming outcomes that impact cellular physiology and trigger adulthood disease. The identification of new therapeutic targets can improve offspring's health management and prevent or overcome adverse consequences of foetal programming. This review summarizes recent biomedical discoveries in the Developmental Origins of Health and Disease (DOHaD) hypothesis and highlight possible developmental programming mechanisms, including prenatal structural defects, metabolic (mitochondrial dysfunction, oxidative stress, protein modification), epigenetic and glucocorticoid signalling-related mechanisms suggesting molecular clues for the causes and consequences of programming of increased susceptibility of offspring to metabolic disease after birth. Identifying mechanisms involved in DOHaD can contribute to early interventions in pregnancy or early childhood, to re-set the metabolic homeostasis and break the chain of subsequent events that could lead to the development of disease.
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Glucocorticoides/fisiologia , Doenças Metabólicas/etiologia , Mitocôndrias/fisiologia , Gravidez/fisiologia , Animais , Epigênese Genética , Feminino , Desenvolvimento Fetal/fisiologia , Feto/fisiologia , HumanosRESUMO
The pressures on honeybee (Apis mellifera) populations, resulting from threats by modern pesticides, parasites, predators and diseases, have raised awareness of the economic importance and critical role this insect plays in agricultural societies across the globe. However, the association of humans with A. mellifera predates post-industrial-revolution agriculture, as evidenced by the widespread presence of ancient Egyptian bee iconography dating to the Old Kingdom (approximately 2400 BC). There are also indications of Stone Age people harvesting bee products; for example, honey hunting is interpreted from rock art in a prehistoric Holocene context and a beeswax find in a pre-agriculturalist site. However, when and where the regular association of A. mellifera with agriculturalists emerged is unknown. One of the major products of A. mellifera is beeswax, which is composed of a complex suite of lipids including n-alkanes, n-alkanoic acids and fatty acyl wax esters. The composition is highly constant as it is determined genetically through the insect's biochemistry. Thus, the chemical 'fingerprint' of beeswax provides a reliable basis for detecting this commodity in organic residues preserved at archaeological sites, which we now use to trace the exploitation by humans of A. mellifera temporally and spatially. Here we present secure identifications of beeswax in lipid residues preserved in pottery vessels of Neolithic Old World farmers. The geographical range of bee product exploitation is traced in Neolithic Europe, the Near East and North Africa, providing the palaeoecological range of honeybees during prehistory. Temporally, we demonstrate that bee products were exploited continuously, and probably extensively in some regions, at least from the seventh millennium cal BC, likely fulfilling a variety of technological and cultural functions. The close association of A. mellifera with Neolithic farming communities dates to the early onset of agriculture and may provide evidence for the beginnings of a domestication process.
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Criação de Abelhas/história , Abelhas , Ceras/análise , Ceras/história , África do Norte , Animais , Arqueologia , Cerâmica/química , Cerâmica/história , Europa (Continente) , Fazendeiros/história , Mapeamento Geográfico , História Antiga , Lipídeos/análise , Lipídeos/química , Oriente Médio , Análise Espaço-Temporal , Ceras/químicaRESUMO
The presence of IL-10, produced either by tumor cells or immunosuppressive cells, is frequently associated with a poor prognosis for cancer progression. It may also negatively impact anticancer treatments, such as immunotherapies, that otherwise would promote the activation of cytotoxic T cells capable of detecting and destroying malignant cells. In the present study, we evaluated a new adjuvant approach for anticancer immunotherapy using a plasmid vector encoding a soluble form of the IL-10 receptor (pIL-10R). pIL-10R was coadministered to mice with a DNA vaccine encoding the type 16 human papillomavirus (HPV-16) E7 oncoprotein genetically fused with glycoprotein D of herpes simplex virus (HSV) (pgDE7h). Immunization regimens based on the coadministration of pIL-10R and pgDE7h enhanced the antitumor immunity elicited in mice injected with TC-1 cells, which express HPV-16 oncoproteins. The administration of the DNA vaccines by in vivo electroporation further enhanced the anticancer effects of the vaccines, leading to the activation of tumor-infiltrating polyfunctional E7-specific cytotoxic CD8+ T cells and control of the expansion of immunosuppressive cells. In addition, the combination of immunotherapy and pIL-10R allowed the control of tumors in more advanced growth stages that otherwise would not be treatable by the pgDE7h vaccine. In conclusion, the proposed treatment involving the expression of IL-10R enhanced the antitumor protective immunity induced by pgDE7h administration and may contribute to the development of more efficient clinical interventions against HPV-induced tumors.
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Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/imunologia , Células Epiteliais/fisiologia , Papillomavirus Humano 16/fisiologia , Imunoterapia/métodos , Neoplasias Experimentais/imunologia , Infecções por Papillomavirus/imunologia , Vacinas contra Papillomavirus/imunologia , Receptores de Interleucina-10/imunologia , Animais , Tolerância Imunológica , Interleucina-10/metabolismo , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Proteínas E7 de Papillomavirus/genética , Vacinas contra Papillomavirus/genética , Receptores de Interleucina-10/genética , Vacinas de DNA , Proteínas do Envelope Viral/genéticaRESUMO
Endothelial dysfunction is associated with several lifestyle-related diseases, including cardiovascular and neurodegenerative diseases, and it contributes significantly to the global health burden. Recent research indicates a link between cardiovascular risk factors (CVRFs), excessive production of reactive oxygen species (ROS), mitochondrial impairment, and endothelial dysfunction. Circulating endothelial progenitor cells (EPCs) are recruited into the vessel wall to maintain appropriate endothelial function, repair, and angiogenesis. After attachment, EPCs differentiate into mature endothelial cells (ECs). Like ECs, EPCs are also susceptible to CVRFs, including metabolic dysfunction and chronic inflammation. Therefore, mitochondrial dysfunction of EPCs may have long-term effects on the function of the mature ECs into which EPCs differentiate, particularly in the presence of endothelial damage. However, a link between CVRFs and impaired mitochondrial function in EPCs has hardly been investigated. In this review, we aim to consolidate existing knowledge on the development of mitochondrial and endothelial dysfunction in the vascular endothelium, place it in the context of recent studies investigating the consequences of CVRFs on EPCs, and discuss the role of mitochondrial dysfunction. Thus, we aim to gain a comprehensive understanding of mechanisms involved in EPC deterioration in relation to CVRFs and address potential therapeutic interventions targeting mitochondrial health to promote endothelial function.
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BACKGROUND: Our group has previously shown that EPHRIN-A1 and SCINDERIN expression by tumor cells rendered them resistant to cytotoxic T lymphocyte-mediated lysis. Whereas the prognostic value of EPHRIN-A1 expression in cancer has already been studied, the role of SCINDERIN presence remains to be established. In the present work, we investigated the prognosis value of EPHRIN-A1 and SCINDERIN expression in head and neck carcinomas. In addition, we monitored the HLA-class I expression by tumor cells and the presence of tumor-infiltrating CD8+ T cells to evaluate a putative correlation between these factors and the survival prognosis by themselves or related to EPHRIN-A1 and SCINDERIN expression. METHODS: Tumor tissue sections of 83 patients with head and neck cancer were assessed by immunohistochemistry for the expression of EPHRIN-A1, SCINDERIN, HLA class I molecules and the presence of CD8+ T cells. RESULTS: No significant prognosis value could be attributed to these factors independently, despite a tendency of association between EPHRIN-A1 and a worse clinical outcome. No prognostic value could be observed when CD8+ T cell tumor infiltration was analyzed combined with EPHRIN-A1, SCINDERIN or HLA class I expression. CONCLUSION: These results highlight that molecules involved in cancer cell resistance to cytotoxic T lymphocytes by themselves are not a sufficient criteria for prognosis determination in cancer patients. Other intrinsic or tumor microenvironmental features should be considered in prognostic evaluation.
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Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Escamosas/metabolismo , Efrina-A1/metabolismo , Gelsolina/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Idoso , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/terapia , Terapia Combinada , Citotoxicidade Imunológica , Feminino , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
Although yeasts belonging to the genus Candida are frequently seen as commensals in the oral cavity, they possess virulence attributes that contribute for pathogenicity. The aims of the present study were to study the prevalence of Candida spp. isolated from the oral cavity of renal transplant recipients and to analyze strains virulence factors. We isolated a total of 70 Candida strains from 111 transplant recipients, and Candida albicans was the most prevalent species (82.86 %). Oral candidiasis was diagnosed in 14.4 % kidney transplant patients, while 11 isolates (15.7 %) corresponded to non-Candida albicans Candida (NCAC) species. C. albicans adhered to a higher extension than NCAC strains. Some isolates of Candida tropicalis were markedly adherent to human buccal epithelial cells and highly biofilm-forming strains. Regarding proteinase activity, Candida orthopsilosis was more proteolytic than Candida metapsilosis. Candida glabrata and Candida dubliniensis showed very low ability to form biofilm on polystyrene microtiter plates. We have demonstrated here diverse peculiarities of different Candida species regarding the ability to express virulence factors. This study will contribute for the understanding of the natural history and pathogenesis of yeasts belonging to the genus Candida in the oral cavity of patients who were submitted to kidney transplant and are under immunosuppressive therapies.
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Candida/classificação , Candida/fisiologia , Portador Sadio/microbiologia , Transplante de Rim , Boca/microbiologia , Transplante , Fatores de Virulência/metabolismo , Adolescente , Adulto , Idoso , Biofilmes/crescimento & desenvolvimento , Brasil , Candida/genética , Candida/isolamento & purificação , Adesão Celular , Criança , Células Epiteliais/microbiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeo Hidrolases/metabolismo , Prevalência , Adulto JovemRESUMO
Gestational diabetes mellitus (GDM) and maternal obesity (MO) increase the risk of adverse fetal outcomes, and the incidence of cardiovascular disease later in life. Extensive research has been conducted to elucidate the underlying mechanisms by which GDM and MO program the offspring to disease. This review focuses on the role of fetoplacental endothelial dysfunction in programming the offspring for cardiovascular disease in GDM and MO pregnancies. We discuss how pre-existing maternal health conditions can lead to vascular dysfunction in the fetoplacental unit and the fetus. We also examine the role of fetoplacental endothelial dysfunction in impairing fetal cardiovascular system development and the involvement of nitric oxide and hydrogen sulfide in mediating fetoplacental vascular dysfunction. Furthermore, we suggest that the L-Arginine-Nitric Oxide and the Adenosine-L-Arginine-Nitric Oxide (ALANO) signaling pathways are pertinent targets for research. Despite significant progress in this area, there are still knowledge gaps that need to be addressed in future research.
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Doenças Cardiovasculares , Diabetes Gestacional , Obesidade Materna , Gravidez , Feminino , Humanos , Diabetes Gestacional/metabolismo , Placenta/metabolismo , Óxido Nítrico/metabolismo , Doenças Cardiovasculares/metabolismo , Obesidade Materna/complicações , Obesidade Materna/metabolismo , Arginina/metabolismoRESUMO
This work presents a data survey regarding the qualitative chemical analysis of drugs seized by the Police in the state of Minas Gerais between July 2017 and June 2022, including an evaluation of labeling of 265 samples of anabolic androgenic steroids (AAS) seized in 2020. The Active Pharmaceutical Ingredients (API) present in the samples were identified through chemical analysis and classified by system Anatomical Therapeutic Chemical (ATC) methods. Analysis of the labeling information for 265 samples of AAS followed the guidance of legislation RDC 71 (2009) from ANVISA. For this study 6355 seized pharmaceuticals underwent qualitative chemical analysis that corresponded to 7739 APIs successfully identified and classified. Among the components studied AAS, psychostimulants, anesthetics, and analgesics were the most commonly examined. AAS seized and tested increased by over 100% and for the majority of the samples analyzed were found to not match the labeling on the packaging. In the meantime, anti-obesity drugs presented a prominent increase of 400% from 2020/1 to 2021/2, during covid-19 quarantine. Seized pharmaceuticals and tests can support information in the planning of public health and safety policies.
Assuntos
COVID-19 , Medicamentos Falsificados , Humanos , Esteróides Androgênicos Anabolizantes , Brasil , Polícia , Congêneres da TestosteronaRESUMO
Obesity incidence has been increasing at an alarming rate, especially in women of reproductive age. It is estimated that 50% of pregnancies occur in overweight or obese women. It has been described that maternal obesity (MO) predisposes the offspring to an increased risk of developing many chronic diseases in an early stage of life, including obesity, type 2 diabetes, and cardiovascular disease (CVD). CVD is the main cause of death worldwide among men and women, and it is manifested in a sex-divergent way. Maternal nutrition and MO during gestation could prompt CVD development in the offspring through adaptations of the offspring's cardiovascular system in the womb, including cardiac epigenetic and persistent metabolic programming of signaling pathways and modulation of mitochondrial metabolic function. Currently, despite diet supplementation, effective therapeutical solutions to prevent the deleterious cardiac offspring function programming by an obesogenic womb are lacking. In this review, we discuss the mechanisms by which an obesogenic intrauterine environment could program the offspring's cardiovascular metabolism in a sex-divergent way, with a special focus on cardiac mitochondrial function, and debate possible strategies to implement during MO pregnancy that could ameliorate, revert, or even prevent deleterious effects of MO on the offspring's cardiovascular system. The impact of maternal physical exercise during an obesogenic pregnancy, nutritional interventions, and supplementation on offspring's cardiac metabolism are discussed, highlighting changes that may be favorable to MO offspring's cardiovascular health, which might result in the attenuation or even prevention of the development of CVD in MO offspring. The objectives of this manuscript are to comprehensively examine the various aspects of MO during pregnancy and explore the underlying mechanisms that contribute to an increased CVD risk in the offspring. We review the current literature on MO and its impact on the offspring's cardiometabolic health. Furthermore, we discuss the potential long-term consequences for the offspring. Understanding the multifaceted effects of MO on the offspring's health is crucial for healthcare providers, researchers, and policymakers to develop effective strategies for prevention and intervention to improve care.
RESUMO
Chronic diseases represent one of the major causes of death worldwide. It has been suggested that pregnancy-related conditions, such as gestational diabetes mellitus (GDM), maternal obesity (MO), and intra-uterine growth restriction (IUGR) induce an adverse intrauterine environment, increasing the offspring's predisposition to chronic diseases later in life. Research has suggested that mitochondrial function and oxidative stress may play a role in the developmental programming of chronic diseases. Having this in mind, in this review, we include evidence that mitochondrial dysfunction and oxidative stress are mechanisms by which GDM, MO, and IUGR program the offspring to chronic diseases. In this specific context, we explore the promising advantages of maternal antioxidant supplementation using compounds such as resveratrol, curcumin, N-acetylcysteine (NAC), and Mitoquinone (MitoQ) in addressing the metabolic dysfunction and oxidative stress associated with GDM, MO, and IUGR in fetoplacental and offspring metabolic health. This approach holds potential to mitigate developmental programming-related risk of chronic diseases, serving as a probable intervention for disease prevention.
Assuntos
Diabetes Gestacional , Obesidade Materna , Complicações na Gravidez , Efeitos Tardios da Exposição Pré-Natal , Gravidez , Feminino , Humanos , Antioxidantes/farmacologia , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Efeitos Tardios da Exposição Pré-Natal/etiologia , Resveratrol/farmacologia , Diabetes Gestacional/prevenção & controle , Complicações na Gravidez/prevenção & controle , Dieta , Obesidade Materna/complicações , Retardo do Crescimento Fetal/prevenção & controle , Doença CrônicaRESUMO
This study presents the development of a simple, fast, and inexpensive approach for the direct analysis of new psychoactive substances (NPS) in seized tablets and blotter paper, with improved sample preservation and increased analytical frequency. Paper triangles were gently rubbed against the surface of the samples containing synthetic drugs and then subjected to analysis by paper spray ionization mass spectrometry (PS-MS). Seized samples containing lysergic acid diethylamide (LSD) and several other substances from the classes of amphetamines, N-benzyl-substituted phenethylamines, synthetic cathinones, and synthetic cannabinoids, were analysed. Three types of paper were tested (filter paper, blotter paper, and synthetic paper) and several combinations of spray solvents were studied for the optimization. All samples were weighed and photographed before and after sequences of analysis in order to attest to the sample preservation. The results revealed that the approach is excellent for sample preservation, with less than 5% of mass loss even after 27 consecutive analyses. Moreover, no significant signal decreases were observed in mass spectrometry (MS) even after the experiments. It was possible to unequivocally identify illicit substances from seized samples (pills and blotter paper). By overcoming the solubilization and wet extraction process used for sample preparation, the waste was restricted to a volume of only 10 µL of solvent for the PS-MS analysis. The main advantage of our approach over existing methods is the sample preparation, which is simple and quick since the samples are just rubbed against the PS paper. This brings enormous benefits in terms of analytical frequency, economy of time and low consumption of solvents. Another important point is that the sample can remain intact for further analysis, which is crucial in forensic analysis.